Gene-based approaches have been used to treat or palliate a variety of disease processes. For example, attempts have been made to use a gene-based approach to target rhythm disorders of the heart (e.g. atrial fibrillation) (AF) (Arora et al. Heart Rhythm. 2008; 5(5S):S55., herein incorporated by reference in its entirety). However, targeting a gene ‘cargo’ to an organ of interest presents a variety of challenges. (Dean et al. Am J Physiol Cell Physiol. August 2005; 289(2):C233-245., Dean et al. Gene therapy. September 2003; 1 0(18): 1608-1615., Donahue. Journal of cardiovascular electrophysiology. May 2007; 18(5):553-559, herein incorporated by reference in their entireties) Systemic gene delivery often results in sub-therapeutic concentrations of a gene in the organ of interest. In addition, systemic delivery carries the risk of unwarranted gene expression in organs that are remote from the region of interest, with the potential for significant side effects.
Catheter systems for local delivery of therapeutic agents have many advantages. Approaches for local delivery of agents at a depth within a tissue are applicable to the heart, pancreas, esophagus, stomach, colon, large intestine, and other tissues which may be accessed via a catheter system. These catheter systems will deliver drugs to the sites where they are most needed, reduce the amount of drug required, increase the therapeutic index, and control the time course of agent delivery. These, in turn, improve the viability of the drugs, lower the amount (and cost) of agents, reduce systemic effects, reduce the chance of drug-drug interactions, lower the risk to patients, and allow the physician to more precisely control the effects induced. Such local delivery may mimic endogenous modes of release, and address the issues of agent toxicity and short half lives.
AF is the most common sustained arrhythmia disturbance, occurring in 0.4% of the general population and in up to 40% of patients with congestive heart failure (CHF). It is a cause of significant morbidity (such as cerebrovascular embolism or ‘stroke’) and also contributes to increased mortality (Balasubramaniam & Kistler. Heart (British Cardiac Society). Jul. 16, 2008., herein incorporated by reference in its entirety). The diagnosis and management of AF have therefore become an important and challenging aspect of cardiovascular medicine. Unfortunately, current approaches to cure this arrhythmia are inadequate (Gerstenfeld et al. Heart Rhythm. February 2006; 3(2): 165-170., herein incorporated by reference in its entirety). The posterior left atrium (PLA) has been shown to play a significant role in the genesis of AF (Haissaguerre et al. Circulation. Mar. 28, 2000; 1 01 (12): 1409-1417., Haissaguerre et al. The New England Journal of Medicine. Sep. 3, 1998; 339(10):659-666, herein incorporated by reference in their entireties). This region has been shown to possess unique structural and electrophysiological characteristics that appear to contribute to substrate for AF. Both sympathetic and parasympathetic activity in the heart is mediated by heterotrimeric G-protein (GαGα3Gα) coupled pathways initiated by G-protein coupled receptors (GPCRs). A gene-based approach can be used to selectively inhibit the G-protein signaling pathways that are critical to autonomic signaling in the atrium (Arora et al. Heart Rhythm. 2007; 4(5S):S9., Arora et al. Heart Rhythm. 2008; 5(5S):S55., herein incorporated by reference in their entireties).